Search

EIF1AX mutations in fatal non-anaplastic thyroid cancer.

List of 410 genes in IMPACT sequencing platform

Supplementary legend

All IMPACT mutation calls. Tumors previously published by Landa et al (1) are highlighted in blue.

Purpose: Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT cancers have not been reported.Experimental Design: We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC.Results: There was a very high prevalence of TERT promoter mutations, comparable with that of ATC, and these co-occurred with BRAF and RAS mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes DLG5–RET and OSBPL1A–BRAF were identified. There was a high frequency of mutations in MED12 and these were mutually exclusive to TERT promoter mutations and also to BRAF and RAS mutations. In addition, a high frequency of mutations in RBM10 was identified and these co-occurred with RAS mutations and PIK3CA mutations. Compared with the PTCs in TCGA, there were higher frequencies of mutations in TP53, POLE, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases.Conclusions: These data support a model, whereby fatal NAT cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of TERT promoter mutations, MED12 mutations, RBM10 mutations, and chromosome 1q gain highlight their likely association with tumor virulence. Clin Cancer Res; 23(19); 5970–80. ©2017 AACR.

Context.— The American Society of Clinical Oncology/College of American Pathologists updated the human epidermal growth factor receptor 2 (HER2) breast carcinoma testing guideline in 2018 to address issues from uncommon HER2 fluorescence in situ hybridization (FISH) results. Based on the 2013 American Society of Clinical Oncology/College of American Pathologists guideline, cases wherein the HER2/chromosome 17 centromere (CEP17) ratio of 2.0 or more with an average HER2 copy number of less than 4.0 were considered in situ hybridization (ISH) positive. Under the 2018 guideline, such cases are classified as ISH Group 2 and are no longer considered eligible for anti-HER2 therapy when the corresponding HER2 immunohistochemistry result is 0, 1+, or 2+. Objective.— To assess the clinical, pathologic, and treatment aspects of patients with ISH Group 2 results. Design.— We retrospectively reviewed HER2 FISH results at our center between January 2012 and December 2014 and identified and characterized cases with ISH Group 2 results. Results.— Thirty-nine cases with ISH Group 2 results from 39 patients were reviewed. Twenty of 39 (51%) patients received anti-HER2 therapy. Patients treated with HER2-targeted therapy were less likely to have hormone receptor–positive tumors, compared with patients without anti-HER2 treatment, though not significantly (P = .30). The only significant difference between the 2 patient groups was receipt of cytotoxic chemotherapy treatment (P < .001). Overall, clinical outcome was similar between the 2 groups (P > .99). Conclusions.— This retrospective study with median follow-up of at least 6 years shows patients with ISH Group 2 tumors had similar clinical outcomes, irrespective of HER2-targeted therapy. Further analysis in the prospective setting would provide valuable data that would potentially inform clinical decision making.

Herein, we present a case of a male patient with breast cancer and a recent history of COVID-19 pneumonia, diagnosed with pseudofungi on pathological examination of lymph nodes after mastectomy. Pseudofungi are septate hyphae-like structures that morphologically mimic fungal elements despite the absence of true mycosis and thus predispose to overtreatment if not properly identified. We report a review of similar cases involving this diagnostic mimicker in the literature.

The International Collaboration on Cancer Reporting was established to internationally unify and standardize the pathologic reporting of cancers based on collected evidence, as well as to allow systematic data collection across institutions and countries to guide cancer care in the future. An expert panel was convened to identify the minimum data set of elements that should be included in cancer reporting from tumors of the nasopharynx and oropharynx. Specifically, there has been a significant change in practice as a result of identifying oncogenic viruses, including human papillomavirus and Epstein-Barr virus, because they preferentially affect the oropharynx and nasopharynx, respectively. For these anatomic sites, when viral association is taken into account, usually reported elements of in situ versus invasive tumor, depth of invasion, and degree of differentiation are no longer applicable. Thus, guidance about human papillomavirus testing in oropharyngeal carcinomas and Epstein-Barr virus testing in nasopharyngeal carcinomas is highlighted. Further, the clinical and the pathologic differences in staging as proposed by the 8th edition of the Union for International Cancer Control are incorporated into the discussion, pointing out several areas of continued study and further elaboration. A summary of the International Collaboration on Cancer Reporting guidelines for oropharyngeal and nasopharyngeal carcinomas is presented, along with discussion of the salient evidence and practical issues.

Standardized, synoptic pathologic reporting for tumors greatly improves communication among clinicians, patients, and researchers, supporting prognostication and comparison about patient outcomes across institutions and countries. The International Collaboration on Cancer Reporting is a nonprofit organization whose mission is to develop evidence-based, universally available surgical pathology reporting data sets. Within the head and neck region, lymph node excisions and neck dissections are frequently performed as part of the management of head and neck cancers arising from the mucosal sites (sinonasal tract, nasopharynx, oropharynx, hypopharynx, oral cavity, and larynx) along with bone tumors, skin cancers, melanomas, and other tumor categories. The type of specimen, exact location (lymph node level), laterality, and orientation (by suture or diagram) are essential to accurate classification. There are significant staging differences for each anatomic site within the head and neck when lymph node sampling is considered, most importantly related to human papillomavirus–associated oropharyngeal carcinomas and mucosal melanomas. Number, size, and site of affected lymph nodes, including guidelines on determining the size of tumor deposits and the presence of extranodal extension and soft tissue metastasis, are presented in the context of prognostication. This review elaborates on each of the elements included in the data set for Nodal Excisions and Neck Dissection Specimens for Head & Neck Tumours.

Early detection and timely treatment of precancerous lesions are hallmarks of successful strategies to prevent deaths due to cancer. Oncolytic viruses are a group of promising anti-cancer agents with wide-ranging experimental and clinical efficacy against solid tumors. Previously, we have shown that NV1066, an oncolytic herpes simplex-1 virus encoding enhanced green fluorescent protein, selectively infects, replicates in, and kills various cancer types. In this study, we sought to determine whether this oncolytic agent can treat precancerous lesions to prevent cancer formation. Using an oral chemical carcinogenesis model in hamsters, we assessed the ability of NV1066 to infect precancerous and cancerous lesions. NV1066 consistently infected dysplastic cells, carcinoma in situ, and squamous cell carcinoma. Animals receiving an intramucosal injection of NV1066 for 7 weeks showed significantly fewer (3-fold) and smaller (4-fold) lesions compared to animals that did not receive viral treatment. Results indicate that infectivity might be dependent on the herpes simplex virus 1 receptor, nectin-1. This study demonstrates that not only can NV1066 treat oral squamous cell carcinoma, but it can also infect and treat premalignant lesions, thus delaying cancer progression. Overall, our study shows the potential of the oncolytic virus NV1066 as a cancer prevention tool. Keywords: cancer prevention, carcinogenesis, early cancer diagnosis, oncolytic virotherapy, oral squamous carcinoma, herpes simplex virus, viral tropism

Background An objective definition of clinically relevant extracapsular nodal spread (ECS) in head and neck squamous cell carcinoma (SCC) is unavailable.

Objective To report the management of a large uterine leiomyoma with diffuse cystic degeneration in a patient with autosomal dominant polycystic kidney disease (ADPKD). Design Case Report. Setting Cleveland Clinic Florida, Department of Gynecology, Section of Minimally Invasive Gynecologic surgery, Weston Florida. Patient(s) A 52-year old woman with ADPKD with a large abdominal mass, abnormal uterine bleeding and symptomatic anemia. Imaging revealed a giant intramural cystic lesion of the uterus compressing the inferior vena cava. Intervention(s) Uterine artery embolization and blood transfusion followed by a computed tomography guided cyst aspiration were performed on admission to alleviate anemia and abdominal pain and distension. Total laparoscopic hysterectomy with bilateral salpingectomy was performed in an outpatient setting. Main Outcome Measure(s) Management of large cystic degeneration of leiomyoma. Results Normal recovery from definitive surgery. Surgical pathology confirmed a benign, cystically dilated leiomyoma. Conclusion This case demonstrates the management of giant intramural cyst lesion of the uterus using a minimally invasive surgical approach, as opposed to emergency surgery via laparotomy. Capsule Large uterine leiomyoma with diffuse cystic degeneration in a patient with autosomal dominant polycystic kidney disease, in which step-wise treatments allows successful minimally invasive hysterectomy., Highlights • Cystic degenerating leiomyoma is a possible rare extra-renal manifestation of autosomal dominant polycystic kidney disease • Third reported and largest uterine cyst in a patient with autosomal dominant polycystic kidney disease in the literature • This case demonstrates successful minimally invasive surgical treatment for a giant degenerating leiomyoma

Purpose: Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT cancers have not been reported. Experimental Design: We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC. Results: There was a very high prevalence of TERT promoter mutations, comparable with that of ATC, and these co-occurred with BRAF and RAS mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes DLG5–RET and OSBPL1A–BRAF were identified. There was a high frequency of mutations in MED12 and these were mutually exclusive to TERT promoter mutations and also to BRAF and RAS mutations. In addition, a high frequency of mutations in RBM10 was identified and these co-occurred with RAS mutations and PIK3CA mutations. Compared with the PTCs in TCGA, there were higher frequencies of mutations in TP53, POLE, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. Conclusions: These data support a model, whereby fatal NAT cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of TERT promoter mutations, MED12 mutations, RBM10 mutations, and chromosome 1q gain highlight their likely association with tumor virulence. Clin Cancer Res; 23(19); 5970–80. ©2017 AACR.

Poorly differentiated thyroid cancer (PDTC) accounts for only 1-15% of all thyroid cancers. Our objective is to report outcomes in a large series of patients with PDTC treated at a single tertiary care cancer center.A total of 91 patients with primary PDTC were treated by initial surgery with or without adjuvant therapy at Memorial Sloan-Kettering Cancer Center from 1986 to 2009. Outcomes were calculated by the Kaplan-Meier method. Clinicopathological characteristics were compared for PDTC patients who died of disease to those who did not by the χ(2) test. Factors predictive of disease-specific survival (DSS) were calculated by univariate and multivariate analysis using the log rank and Cox proportional hazards method, respectively.With a median follow-up of 50 months, the 5-year overall survival and DSS were 62 and 66%, respectively. The 5-year locoregional and distant control were 81 and 59%, respectively. Of 27 disease-specific deaths, 23 (85%) were due to distant disease. Age ≥ 45 years, pathological tumor size4 cm, extrathyroidal extension, higher pathological T stage, positive margins, and distant metastases (M1) were predictive of worse DSS on univariate analysis. Multivariate analysis showed that only pT4a stage and M1 were independent predictors of worse DSS.With appropriate surgery and adjuvant therapy, excellent locoregional control can be achieved in PDTC. Disease-specific deaths occurred due to distant metastases and rarely due to uncontrolled locoregional recurrence in this series.

The aim of the present study is to correlate non-invasive, pretreatment biological imaging (dynamic contrast enhanced-MRI [DCE-MRI] and proton magnetic resonance spectroscopy [(1)H-MRS]) findings with specific molecular marker data in neck nodal metastases of head and neck squamous cell carcinoma (HNSCC) patients. Pretreatment DCE-MRI and (1)H-MRS were performed on neck nodal metastases of 12 patients who underwent surgery. Surgical specimens were analyzed with immunohistochemistry (IHC) assays for: Ki-67 (reflecting cellular proliferation), vascular endothelial growth factor (VEGF) (the "endogenous marker" of tumor vessel growth), carbonic anhydrase (CAIX), hypoxia inducible transcription factor (HIF-1?), and human papillomavirus (HPV). Additionally, necrosis was estimated based on H&E staining. The Spearman correlation was used to compare DCE-MRI, (1)H-MRS, and molecular marker data. A significant correlation was observed between DCE-MRI parameter std(k(ep)) and VEGF IHC expression level (rho=0.81, p=0.0001). Furthermore, IHC expression levels of Ki-67 inversely correlated with std(K(trans)) and std(v(e)) (rho=-0.71; p=0.004, and rho=-0.73; p=0.003, respectively). Other DCE-MRI, (1)H-MRS and IHC values did not show significant correlation. The results of this preliminary study indicate that the level of heterogeneity of perfusion in metastatic HNSCC seems positively correlated with angiogenesis, and inversely correlated with proliferation. These results are preliminary in nature and are indicative, and not definitive, trends portrayed in HNSCC patients with nodal disease. Future studies with larger patient populations need to be carried out to validate and clarify our preliminary findings.

BACKGROUND: For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high-dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation. METHODS: Planned treatment consisted of definitive intensity-modulated radiation therapy (IMRT) (total, 70 grays) with concurrent cisplatin (50 mg/m2 on days 1, 2, 22, 23, 43, and 44) and bevacizumab (15 mg/kg on days 1, 22, and 43). The primary endpoint was 2-year progression-free survival (PFS), and overall survival (OS) was a secondary endpoint. RESULTS: Forty-two previously untreated patients (34 men and 8 women; median age, 55 years; range, 27-75 years) with stage III through IV HNSCC without distant metastasis (oropharyngeal carcinoma, 39 patients; laryngeal carcinoma, 3 patients) were treated. Human papillomavirus (HPV) status by was determined by in situ hybridization (HPV positive, 16 patients; HPV negative, 14 patients, unknown HPV status, 12 patients). The toxicities (determined according to version 3.0 of Common Terminology Criteria for Adverse Events Common) that were experienced by all patients (any grade) were mucositis, lymphopenia, leukopenia, throat pain, fatigue, and anemia. There were 2 treatment-related deaths, including 1 sudden death and 1 death from aspiration pneumonia. The median follow-up was approximately 31.8 months (range

Granulomatous mastitis (GM) is a relatively uncommon inflammatory breast lesion with multiple suggested etiologies. Although most GM cases show association with lactation and pregnancy, a minority of cases have been linked to hyperprolactinemia caused by either dopamine antagonist medications or with intracranial lesions, such as pituitary adenoma. The goal of this study is to review the GM cases reported in the literature with a specific emphasis on those cases associated with hyperprolactinemia and prolactinomas and to identify cases of GM seen at the Cleveland Clinic Florida which demonstrate co-occurrences of GM and intracranial lesions. CoPath and Epic data bases at Cleveland Clinic Florida were searched for cases describing inflammatory breast lesions in patients with pituitary pathology. Chart reviews were conducted and pertinent medical history was extracted for case reports. H&E-stained paraffin-embedded sections retrieved from Cleveland Clinic Florida pathology storage were evaluated by light microscopy. Four cases showing a co-occurrence of GM and hyperprolactinemia were consequently identified. A prolactin-secreting pituitary adenoma was present in two of the three GM cases. The third case demonstrated a concomitant craniopharyngioma, which was also associated with a rise in serum prolactin. This phenomenon was presumably attributable to compression, resulting in compromised transport of dopamine to the adenohypophysis and subsequent disinhibition of prolactin secretion by lactotrophs. The fourth patient with GM had a similar history of elevated prolactin. Classical histopathological features of GM were found in all four cases, including noncaseating granulomas, multinucleated giant cells, epithelioid histiocytes, and chronic inflammation. Intriguingly, complete resolution of inflammatory breast lesions along with normalization of prolactin levels occurred following the surgical excision of the craniopharyngioma, suggesting that intracranial lesion-induced hyperprolactinemia might be directly causal in GM. Therefore, the authors would suggest screening for pituitary tumors and evaluate prolactin levels in the workup of GM patients without a recent history of lactation and pregnancy and no other identified etiology.

Management of the neck in patients treated with primary chemoradiation for cancer of the laryngopharynx with a clinically positive neck remains an area of controversy. The neck may be managed in 1 of 3 ways: by observation, by planned neck dissection, or by salvage neck dissection. Observation of the neck can be done in patients who have a complete or near-complete response to treatment and have a negative positron emission tomography (PET) scan result. Evidence for this approach comes from recent studies that have reported low regional recurrence rates.1–6 Planned neck dissection was carried out in the past in patients with N2 and N3 neck disease irrespective of the response to chemoradiation. The neck dissection was carried out 6 weeks after completion of chemoradiation; this approach had the advantage of carrying out the neck dissection before the onset of fibrosis, thereby making the neck dissection technically similar in complexity to a nonchemoradiation neck dissection. Evidence for a policy of planned neck dissection comes from studies that have shown the presence of tumor in neck dissection specimens in patients who have complete or near-complete radiologic and clinical response in the neck.4,7–10 Before the introduction of fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning, planned neck dissection was a common method for managing the neck after chemoradiation. Some groups still practice this policy because of limitations or unavailability of PET. However, in general, most centers now reserve neck dissection for salvage for residual or recurrent neck disease. Salvage neck dissection is normally carried out if there is clinical or radiologic evidence of neck disease after completion of chemoradiation. Before 2005, our policy was to assess response by clinical examination and CT imaging at 6 to 12 weeks after completion of chemoradiation. However, since 2005, we have been using 18FDG-PET for the assessment of tumor response. The 18FDG-PET is usually carried out at 12 weeks after completion of chemoradiation to minimize any false-positive results from residual inflammation from chemoradiation. Salvage neck dissection in patients who have neck disease as detected by PET is therefore carried out 12 weeks after chemoradiation. This has the disadvantage of making the operation technically more difficult because of the onset of fibrosis. As a consequence, some have advocated the use of selective and superselective salvage neck dissections in these patients.11–14 Clearly there is evidence in the literature to support the practice of planned, as well as salvage neck dissection. However, there is little in the literature that describes what the impact of viable tumor in such neck dissection specimen has on prognosis. In this study, we have examined our own experience of patients undergoing comprehensive neck dissection either as a planned procedure or salvage procedure in the time period before our routine use of PET. The objective was to determine whether viable tumor had a negative impact on prognosis, even after removal of residual tumor by neck dissection.

Originally identified as an oncogene activated by amplification in squamous cell carcinomas, several lines of evidence now suggest that squamous cell carcinoma-related oncogene (SCCRO; aka DCUN1D1) may play a role in the pathogenesis of a wide range of human cancers including gliomas. SCCRO's oncogenic function is substantiated by its ectopic expression, resulting in transformation of cells in culture and xenograft formation in nude mice. The aim of this study was to assess the in vivo oncogenicity of SCCRO in a murine model. Ubiquitous expression of SCCRO resulted in early embryonic lethality. Because SCCRO overexpression was detected in human gliomas, its in vivo oncogenic activity was assessed in an established murine glioma model. Conditional expression of SCCRO using a replication-competent ASLV long terminal repeat with splice acceptor/nestin-(tumor virus-A) tv-a model system was not sufficient to induce tumor formation in a wild-type genetic background, but tumors formed with increasing frequency and decreasing latency in facilitated background containing Ink4a deletion alone or in combination with PTEN loss. Ectopic expression of SCCRO in glial progenitor cells resulted in lower-grade gliomas in Ink4a-/- mice, whereas its expression in Ink4a-/-/PTEN-/- background produced high-grade glioblastoma-like lesions that were indistinguishable from human tumors. Expression of SCCRO with platelet-derived growth factor-beta (PDGF-β) resulted in an increased proportion of mice forming glioblastoma-like tumors compared with those induced by PDGF-β alone. This work substantiates SCCRO's function as an oncogene by showing its ability to facilitate malignant transformation and carcinogenic progression in vivo and supports a role for SCCRO in the pathogenesis of gliomas and other human cancers.

The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown.We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function.Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P.001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P.001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice.These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.

Predictive role of undetectable thyroglobulin (Tg) in patients with poorly differentiated thyroid carcinoma (PDTC) is unclear. Our goal was to report on Tg levels following total thyroidectomy and adjuvant RAI in PDTC patients and to correlate Tg levels with recurrence.Forty patients with PDTC with no distant metastases at presentation (M0) and managed by total thyroidectomy and adjuvant RAI were identified from a database of 91 PDTC patients. Of these, 31 patients had Tg values recorded and formed the basis of our analysis. A nonstimulated Tg level1 ng/ml was used as a cutoff point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by χ (2) test. Recurrence-free survival (RFS) stratified by postop Tg level was calculated by Kaplan-Meier method and compared by log-rank test.Twenty patients had undetectable Tg (1 ng/ml) and 11 had detectable Tg (≥1 ng/ml; range 2-129 ng/ml) following surgery. After adjuvant RAI, 24 patients had undetectable Tg (1 ng/ml) and 7 had detectable Tg (≥1 ng/ml; range 1-57 ng/ml). Patients with undetectable Tg were less likely to have pathologically positive margins compared to those with detectable Tg (33 vs. 72 % respectively; p = 0.03). Patients with undetectable Tg levels had better 5-year regional control and distant control than patients with detectable Tg level (5-year regional recurrence-free survival 96 vs. 69 %; p = 0.03; 5-year distant recurrence-free survival 96 vs. 46 %, p = 0.11).Postoperative thyroglobulin levels in subset of patients with PDTC appear to have predictive value for recurrence. Patients with undetectable Tg have a low rate of recurrence.

Retinoblastoma is the most common primary cancer of the eye in children. The incidence of second tumors in survivors of bilateral retinoblastoma and in survivors of unilateral retinoblastoma who presumably carry a germline RB1 mutation is documented. This paper describes the previously unrecognized association of sinonasal adenocarcinoma as a second malignancy in retinoblastoma survivors. We present three cases who received radiation therapy as a part of their treatment and developed sinonasal adenocarcinoma as a second malignancy. Sinonasal adenocarcinoma should be considered as a second malignancy in retinoblastoma survivors who present with vague sinus symptoms.

Follicular dendritic cell tumors are rare cancers of the lymph nodes of the head and neck. Despite a relatively high rate of recurrence, these neoplasms have a limited impact on the airways because they can be potentially cured by surgical resection. We present the case of a young woman with an unresectable follicular dendritic cell tumor involving the paratracheal region causing upper airway obstruction and respiratory failure. This malignant tumor created numerous management dilemmas and therapeutic challenges related to the unstable airway and the need for tracheal stenting to bypass the airway obstruction.

Andrew G. Huvos was born in communist Budapest, Hungary, in March of 1934. At twenty-four he immigrated to New York City, working as a cytotechnologist at Delafield Hospital. Dr. Huvos attended the University of Gottingen Medical School in Germany, where he was awarded his MD degree. He completed a 1-year internship at New York Hospital, going on to Residency at Delafield Hospital and Fellowship at Presbyterian Hospital. Dr. Huvos ascended through the ranks to Attending Pathologist and Member at Memorial Hospital for Cancer and Allied diseases, at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. Concurrently, he was appointed to Weill Medical College of Cornell University, where he was Professor of Pathology for over two decades. Dr. Huvos was an editorial referee for over half a dozen highly esteemed publications, including the New England Journal of Medicine and Cancer. He trained over a thousand oncological surgical pathology fellows, head and neck fellows, and surgeons. Dr. Huvos spent nearly 40 years at MSKCC and his career was accompanied by his authorship of 388 peer-reviewed publications and eighteen book chapters. His legacy leaves behind a generation of pathologists who have greatly benefited from his tutelage.

Retinoblastoma is the most common primary cancer of the eye in children. The incidence of second tumors in survivors of bilateral retinoblastoma and in survivors of unilateral retinoblastoma who presumably carry a germline RB1 mutation is documented. This article describes the previously unrecognized association of sinonasal adenocarcinoma as a second malignancy in retinoblastoma survivors. We present three cases who received radiation therapy as a part of their treatment and developed sinonasal adenocarcinoma as a second malignancy. Sinonasal adenocarcinoma should be considered as a second malignancy in retinoblastoma survivors who present with vague sinus symptoms.

To characterize the incidence and pattern of neural invasion (NI) in patients with cancers of the paranasal sinuses and anterior skull base.Retrospective study.A tertiary referral cancer center.The study included 208 patients with cancer of the paranasal sinuses. Patients with brain invasion or neurogenic tumors were excluded.Analysis of clinical and pathologic data on patients with cancer of the paranasal sinuses.Forty-one specimens (20%) had evidence of NI. Sinonasal undifferentiated, adenoid cystic, and squamous cell carcinoma had a high propensity for NI, whereas melanoma and sarcoma rarely invaded nerves. Intraneural invasion was found in 32% of these cases, and 34% invaded more than 1 cm distal to the tumor. Neural invasion was associated with a high rate of positive margins, maxillary origin, and previous surgical treatment (P.04) but not with stage, orbital invasion, or dural invasion. Patients with NI were more likely to undergo adjuvant radiotherapy (P = .003), which significantly improved survival in patients with minor salivary gland carcinomas (P = .04). Multivariate analysis showed that pathologic evidence of NI was not an independent predictor of outcome.Paranasal carcinomas have high propensity for NI, whereas melanoma and sarcoma rarely invade nerves. Patterns of NI include both perineural and intraneural invasion. Neural invasion is associated with positive margins, maxillary origin, and previous surgery.

Context.—Necrotizing sialometaplasia is a benign, self-limited lesion of both major and minor salivary glands, although more commonly the latter. It can represent a diagnostic dilemma and may be mistaken for a malignant neoplasm, such as mucoepidermoid carcinoma, as well as invasive squamous cell carcinoma. A major causal relationship has been ascribed to ischemia. Bulimia, an eating disorder with increasing prevalence in our society, may also be an underlying underreported cause. Objective.—To discuss the potential pathogenesis, diagnostic pitfalls, and the application of immunohistochemistry as an aid in the diagnosis of necrotizing sialometaplasia. Data Sources.—This report uses a previously published case history for illustrative purposes and a review of the current literature. Conclusions.—The diagnosis of necrotizing sialometaplasia may be difficult and is reliant upon a well-oriented biopsy section and a complete clinical history. Diagnosis may be further supplemented via immunohistochemistry, demonstrating focal to absent immunoreactivity for p53, low immunoreactivity for MIB1 (Ki-67), and the presence of 4A4/p63- and calponin-positive myoepithelial cells. Interpreted in context collectively, these findings may be helpful adjuncts in the diagnosis of necrotizing sialometaplasia; nonetheless, to date, hematoxylin-eosin staining remains the gold standard.

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.

There is continuous debate regarding the optimal classification, prognosis, and treatment of the follicular variant of papillary thyroid carcinoma (FVPTC). The objective of this study was to assess the behavior of FVPTC, especially its encapsulated form, and shed more light on its true position in the classification scheme of well differentiated thyroid carcinoma.All patients with FVPTC, follicular thyroid adenoma (FTA), and follicular thyroid carcinoma (FTC) who were diagnosed between 1980 and 1995 were reviewed and reclassified according to the currently accepted definition of FVPTC. The tumors were separated into encapsulated and nonencapsulated (infiltrative/diffuse) types. Encapsulated tumors were subdivided further into tumors with or without capsular/vascular invasion. These different subtypes of FVPTC were correlated with outcome and with other clinicopathologic parameters.After review by 4 pathologists, 78 patients were included in the study. Sixty-one of 78 patients (78%) had encapsulated tumors (18 invasive, 43 noninvasive), and 17 patients had nonencapsulated tumors (infiltrative/diffuse). The gender distribution, age at presentation, and tumor size did not differ between patients with encapsulated and nonencapsulated FVPTC. Patients who had encapsulated FVPTC had a significantly lower rate of marked intratumor fibrosis (18%), extrathyroid extension (5%), and positive margins (2%) compared with patients who had nonencapsulated tumors (88%, 65%, and 50% respectively; P.0001). Regional lymph node metastases were present in 14 of 78 patients (18%), and no patients had distant metastases. The lymph node metastatic rate was significantly higher in patients who had nonencapsulated tumors (11 of 17 patients; 65%) compared with patients who had encapsulated neoplasms (3 of 61 patients; 5%; P.0001). In addition, lymph node metastases were not detected in any noninvasive, encapsulated FVPTCs. With a median follow-up of 10.8 years, only 1 patient developed a recurrence, which occurred in an encapsulated FVPTC that had numerous invasive foci. None of the patients with noninvasive, encapsulated FVPTCs developed recurrences, including 31 patients who underwent lobectomy alone, with a median follow-up of 11.1 years.FVPTC appeared to be a heterogeneous disease composed of 2 distinct groups: an infiltrative/diffuse (nonencapsulated) subvariant, which resembles classic papillary carcinoma in its metastatic lymph node pattern and invasive growth, and an encapsulated form, which behaves more like FTA/FTC. Patients who had noninvasive, encapsulated FVPTCs did not develop lymph node metastases or recurrences and could be treated by lobectomy alone. If the current findings are confirmed, then strong consideration should be given to reclassifying encapsulated FVPTC as an entity that is close to the FTA/FTC class of tumors.

Objective To describe the clinicopathologic and radiologic features of solitary fibrous tumors of the head and neck. Design Retrospective analysis. Setting Tertiary referral center that performs head and neck surgical oncology. Patients Twelve patients with solitary fibrous tumors of the head and neck identified from the pathology and soft tissue tumor databases at Memorial Sloan-Kettering Cancer Center, New York, NY, from 1990 to 2004. All cases were reviewed by 3 experienced pathologists, 1 of whom is an experienced soft tissue tumor pathologist. The diagnosis was confirmed by microscopic features on hematoxylin-eosin staining and by positive staining for CD34 and Bcl2 on immunohistochemical analysis. Tumors were scored for mitotic activity, cellularity, nuclear pleomorphism, necrosis, and the presence of a malignant component. Details on patient characteristics, tumor characteristics, previous treatment and surgery, adjuvant treatment, and outcome were recorded from clinical records. Results Solitary fibrous tumors occurred in patients over a wide age range (27-78 years; median age, 52 years). Seven patients (58%) were women, and 5 (42%) were men. Most tumors presented as a slow-growing painless mass with a duration ranging from 2 months to 5 years. The tumors ranged from 1 × 1 cm to 6 × 5 cm. Patients presented with a subcutaneous mass of the scalp or face in 4 cases, intraoral mass in 4, sinonasal mass in 3, and paraspinal mass in 1. Computed tomographic and/or magnetic resonance imaging scans of 7 of the 12 patients showed well-circumscribed tumors that enhanced strongly with contrast. Treatment for all of the patients was surgical resection. Pathologic findings showed that 9 tumors were benign and 3 were malignant. Three patients had a positive surgical resection margin. All patients were alive at a median follow-up of 8 months (range, 1-76 months). Local recurrence occurred in 1 patient who had positive surgical margins 3 years after the initial surgery. Conclusions Solitary fibrous tumors of the head and neck region are rare and most commonly benign. The diagnosis depends on microscopic and immunohistochemical features, although imaging may help. Patients with these tumors can be safely treated with local excision, but tumors with positive margins require close follow-up over several years owing to the potential for late local recurrence.

(18)F-FDG PET has a high accuracy in staging head and neck cancer, but its role in patients with clinically and radiographically negative necks (N0) is less clear. In particular, the value of combined PET/CT has not been determined in this group of patients.In a prospective study, 31 patients with oral cancer and no evidence of lymph node metastases by clinical examination or CT/MRI underwent (18)F-FDG PET/CT before elective neck dissection. PET/CT findings were recorded by neck side (left or right) and lymph node level. PET/CT findings were compared with histopathology of dissected nodes, which was the standard of reference.Elective neck dissections (26 unilateral, 5 bilateral; a total of 36 neck sides), involving 142 nodal levels, were performed. Only 13 of 765 dissected lymph nodes harbored metastases. Histopathology revealed nodal metastases in 9 of 36 neck sides and 9 of 142 nodal levels. PET was TP in 6 nodal levels (6 neck sides), false-negative in 3 levels (3 neck sides), true-negative in 127 levels (23 neck sides), and false-positive in 6 levels (4 neck sides). The 3 false-negative findings occurred in metastases smaller than 3 mm or because of inability to distinguish between primary tumor and adjacent metastasis. TP and false-positive nodes exhibited similar standardized uptakes (4.8 +/- 1.1 vs. 4.2 +/- 1.0; P = not significant). Sensitivity and specificity were 67% and 85% on the basis of neck sides and 67% and 95% on the basis of number of nodal levels, respectively. If a decision regarding the need for neck dissection had been based solely on PET/CT, 3 false-negative necks would have been undertreated, and 4 false-positive necks would have been overtreated.(18)F-FDG PET/CT can identify lymph node metastases in a segment of patients with oral cancer and N0 neck. A negative test can exclude metastatic deposits with high specificity. Despite reasonably high overall accuracy, however, the clinical application of PET/CT in the N0 neck may be limited by the combination of limited sensitivity for small metastatic deposits and a relatively high number of false-positive findings. The surgical management of the N0 neck should therefore not be based on PET/CT findings alone.

BACKGROUND Follicular carcinomas of the thyroid gland, including its oncocytic variant (so-called Hurthle cell carcinoma), are subdivided into the indolent encapsulated (“minimally invasive”) and the clinically aggressive widely invasive tumors. There are, however, cases of encapsulated follicular carcinoma that recur and metastasize. Identifying these cases at the time of diagnosis is crucial for prognostic and therapeutic considerations. Because to the authors' knowledge most studies do not focus exclusively on the encapsulated Hurthle cell carcinoma (EHC), the current study attempted to identify predictors of recurrence in EHC. METHODS A tumor was defined as EHC if it was encapsulated, macroscopically well defined with microscopic but no macroscopic evidence of vascular or capsular invasion, and composed of >75% follicular oncocytic cells. Retrospective chart review and microscopic examination identified 50 primary tumors meeting the above criteria at the Memorial Sloan-Kettering Cancer Center between 1967 and 2005. The cases were analyzed for various histologic and clinical parameters. Each parameter was correlated with recurrence-free survival (RFS). RESULTS Seven of 50 (14%) patients developed disease recurrence. All patients who developed recurrence were found to have a high number of foci of vascular invasion (≥ 4). In univariate analysis, ≥ 4 foci of vascular invasion (P 4 cm (P = .049), the presence of mitosis (P = .018), and a solid/trabecular growth pattern (P = .009) were found to be correlated with a decreased RFS. Extensive capsular invasion, gender, and age did not confer a statistically higher recurrence rate. The finding of a solid/trabecular growth and mitosis correlated with the presence of numerous foci (≥ 4) of vascular invasion (P = .01 and P = .005, respectively). CONCLUSIONS A diligent search for vascular invasion is recommended in EHC that display mitosis or a solid/trabecular growth pattern. The presence of ≥ 4 foci of vascular invasion should alert the pathologist and the clinician to a significantly higher risk of recurrence in EHC. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND Poorly differentiated thyroid carcinomas (PDTC) occupy an intermediate position at the prognostic level on the spectrum of thyroid carcinoma progression. However, their histologic definition is controversial. The objective of the current study was to assess the prognostic significance of PDTC defined on the basis of mitosis and necrosis and search for prognostic markers within this group of tumors that are predictive of overall survival (OS) and progression-free survival (PFS). METHODS PDTC was defined as thyroid carcinoma with follicular cell differentiation at the histologic and/or immunohistochemical levels and displaying tumor necrosis and/or ≥ 5 mitoses per 10 high-power fields (×400). Retrospective chart review and microscopic examination identified 58 patients with primary tumors meeting the above criteria and seen at the Memorial Sloan-Kettering Cancer Center between 1992 and 2004. These 58 patients were analyzed for various histologic, clinical, and imaging parameters. Each parameter was correlated with OS and PFS. RESULTS Of the 58 patients studied, 22 (38%) patients died of disease with a 5-year OS rate of 60%. Forty-three of the 58 patients (74%) developed disease recurrence or disease progression, with a 5-year PFS rate of 25%. The median follow-up for the entire patient population was 42.6 months (range, 4–205 mos). A tumor size > 4 cm was found to be correlated with a decreased PFS time (P < 0.001). Those tumors with a capsule demonstrated a significantly improved OS compared with unencapsulated tumors (P = 0.001). The extent of capsular invasion was found to be a significant adverse factor for PFS (P = 0.05). The presence of extrathyroid extension into perithyroid soft tissue was found to be correlated with a decreased OS (P = 0.001) and PFS (P = 0.004). Of 27 patients with distant metastasis, 19 (70%) had concentrated radioactive iodine (RAI) at their metastatic sites. On multivariate analysis, extrathyroid extension and tumor size emerged as the only significant variables in predicting PFS (P = 0.04 and P = 0.01, respectively) whereas extrathyroid extension was found to be the sole independent prognostic factor for OS (P = 0.01). Growth pattern and cell type did not appear to influence outcome. CONCLUSIONS PDTC defined on the basis of mitosis and necrosis constitutes a group of tumors that is more aggressive and homogeneous than PDTC defined by growth pattern. Within this group of patients, microstaging (tumor size, the extent of capsular invasion, and, especially, extrathyroid extension), and not growth pattern or cell type, is able to stratify patients into different prognostic categories. RAI uptake occurs in a significant number of patients with PDTC. Cancer 2006. © 2006 American Cancer Society.

Lung neoplasms commonly develop in patients previously treated for head and neck carcinomas. The derivation of these tumors, either as new primary lung cancers or as metastatic head and neck cancers, is difficult to establish based on clinical or histopathologic criteria since both are squamous cell carcinomas and have identical features under light microscopy. However, this distinction has significant treatment and prognostic implications. Gene expression profiling was performed on a panel of 52 sequentially collected patients with either primary lung (n = 21) or primary head and neck (n = 31) carcinomas using the Affymetrix HG_U95Av2 high-density oligonucleotide microarray. Unsupervised hierarchical clustering with Ward linkage and the Pearson correlation metric was performed. To assess robustness, bootstrap resampling was performed with 1,000 iterations. A t test of the normalized values for each gene was used to determine the genes responsible for segregating head and neck from lung primary carcinomas, and those with the most differential expression were used for later analyses. In the absence of a large “test” set of tumors, we used a supervised leave-one-out cross-validation to test how well we could predict the tumor origin. Once a gene expression profile was established, 12 lung lesions taken from patients with previously treated head and neck cancers were similarly analyzed by gene expression profiling to determine their sites of origin. Unsupervised clustering analysis separated the study cohort into two distinct groups which reliably remained segregated with bootstrap resampling. Group 1 consisted of 30 tongue carcinomas. Group 2 consisted of 21 lung cancers and 1 tongue carcinoma. The clustering was not changed even when normal lung or tongue profiles were subtracted from the corresponding carcinomatous lesions, and a leave-one-out cross-validation showed a 98% correct prediction (see Supplementary Data 1). A minimum set of 500 genes required to distinguish these groups was established. Given the ability to segregate these lesions using molecular profiling, we analyzed the lung tumors of undetermined origin. All cases clearly clustered with either lung or tongue tumor subsets, strongly supporting our hypothesis that this technique could elucidate the tissue of origin of metastatic lesions. Although histologically similar, squamous cell carcinomas have distinct gene expression profiles based on their anatomic sites of origin. Accordingly, the application of gene expression profiling may be useful in identifying the derivation of lung nodules and consequently enhances treatment planning.

Fanconi anemia is an autosomal recessive disorder characterized by congenital malformations, bone marrow failure, and the development of squamous cell carcinomas (SCCs) and other cancers. Recent clinicopathologic evidence has raised the possibility that an environmental factor such as human papillomavirus (HPV) may be involved in the pathogenesis of SCCs in Fanconi anemia patients. Given the high prevalence of p53 mutations in SCCs among the general population and the lack of p53 mutations in HPV-related carcinogenesis, we evaluated the role of HPV and p53 mutations and polymorphisms in SCC from Fanconi anemia patients. We used polymerase chain reaction (PCR) screening and real-time PCR to detect and quantify HPV DNA in DNA extracted from microdissected SCCs obtained from 24 Fanconi anemia patients (n = 25 SCCs; case subjects) and 50 age-, sex-, and tumor site-matched SCC patients without Fanconi anemia (n = 50 SCCs; control subjects). We PCR-amplified and sequenced exons 4-9 of the p53 gene from SCC DNA. We detected HPV DNA in 84% of the SCC specimens from the case subjects and in 36% of the SCC specimens from the control subjects (P

A12-year-old previously healthy girl developed syncope when walking at school. When she was seen in the emergency department, her heart rate was 115 bpm, the precordial impulse was active, and a thrill was palpated. Third and fourth heart sounds were heard. A grade 4/6 systolic ejection murmur was heard at the …

Objective To report our experience in treating patients with malignant minor salivary gland tumors of the larynx. Design Thirty-three-year retrospective study. Setting Tertiary referral center specializing in head and neck surgery. Patients Twelve patients with malignant minor salivary gland tumors of the larynx were identified from a search of the institutional databases and pathology records at Memorial Sloan-Kettering Cancer Center, New York, NY, between the years 1970 and 2003. All slides were independently reviewed by 2 pathologists (R.G. and D.C.). Details on patient and tumor characteristics, as well as treatment and surgical outcome, were recorded. Results Ten patients (83%) had adenoid cystic carcinoma and 2 (17%) had myoepithelial carcinoma. Five (42%) were located in the supraglottis and 7 (58%) in the subglottis. Ten (83%) had surgery (6 with adjuvant radiotherapy) and 2 (17%) were treated with radiotherapy alone. Of the 10 patients who had surgery, total laryngectomy was required in 6 (60%), supraglottic horizontal laryngectomy in 2 (20%), and cricotracheal resection in 2 (20%). With a median follow-up of 55 months (range, 1-194 months), 10 patients are alive, 6 of whom have no evidence of disease. Seven patients (58%) developed recurrent disease, 2 of whom had local recurrence alone, 1 had regional recurrence alone, 3 had distant recurrence alone, and 1 had local and distant recurrence. Conclusions Up to 60% of patients with malignant minor salivary gland tumors of the larynx will develop recurrent disease locally, regionally, or at distant sites. In adenoid cystic carcinoma, regional recurrence is rare, but distant recurrence is common and may occur up to 10 years after the index therapy. For both adenoid cystic and myoepithelial carcinoma, partial surgery is possible in selected cases, but because of the high propensity for submucosal spread and perineural and lymphovascular invasion, total laryngectomy is usually recommended.

Background The present study is aimed at identifying potential candidate genes as prognostic markers in human oral tongue squamous cell carcinoma (SCC) by large scale gene expression profiling. Methods The gene expression profile of patients (n=37) with oral tongue SCC were analyzed using Affymetrix HG_U95Av2 high-density oligonucleotide arrays. Patients (n=20) from which there were available tumor and matched normal mucosa were grouped into stage (early vs. late) and nodal disease (node positive vs. node negative) subgroups and genes differentially expressed in tumor vs. normal and between the subgroups were identified. Three genes, GLUT3, HSAL2, and PACE4, were selected for their potential biological significance in a larger cohort of 49 patients via quantitative real-time RT-PCR. Results Hierarchical clustering analyses failed to show significant segregation of patients. In patients (n=20) with available tumor and matched normal mucosa, 77 genes were found to be differentially expressed (P< 0.05) in the tongue tumor samples compared to their matched normal controls. Among the 45 over-expressed genes, MMP-1 encoding interstitial collagenase showed the highest level of increase (average: 34.18 folds). Using the criterion of two-fold or greater as overexpression, 30.6%, 24.5% and 26.5% of patients showed high levels of GLUT3, HSAL2 and PACE4, respectively. Univariate analyses demonstrated that GLUT3 over-expression correlated with depth of invasion (PHSAL2 was positively associated with depth of invasion (P=0.015) and advanced T stage (P=0.047). In survival studies, only GLUT3 showed a prognostic value with disease-free (P=0.049), relapse-free (P=0.002) and overall survival (P=0.003). PACE4 mRNA expression failed to show correlation with any of the relevant parameters. Conclusion The characterization of genes identified to be significant predictors of prognosis by oligonucleotide microarray and further validation by real-time RT-PCR offers a powerful strategy for identification of novel targets for prognostication and treatment of oral tongue carcinoma.